OBJECTIVE: To demonstrate a framework for calculating daily dose distributions for proton therapy in a timeframe amenable to online evaluation using CT-on-Rails.
METHODS: Tasks associated with calculation of daily dose are fully automated. A rigid registration between daily and planning images is used to propagate beams and targets for calculation of daily dose; additionally, risk structures are propagated using deformable registration to facilitate online evaluation. An end-to-end constancy test was carried out using a pelvis phantom containing a simulated target and bladder contour. 97 Daily fan-beam CT data sets associated with 10 clinical patients were processed to demonstrate feasibility and utility of online evaluation. Computing times and dosimetric differences are reported.
RESULTS: The phantom constancy test took 62 s to complete with no notable discrepancies in the registrations or calculated dose. Max doses were identical for target and bladder contours on initial and repeat scans (359 and 310 cGy (RBE) respectively). Total processing time for 97 daily patient images averaged 154.6 s (73.0 - 222.0 s; SD = 31.8 s). On average, dose calculation accounted for 35 % of total processing time. Average differences in D95 for target contours was 1.5 % (SD = 1.6 %) with a max decrease of 5.9 % on a single daily image.
CONCLUSIONS: Daily dose can be automatically calculated in a timeframe amenable to online evaluation using scanner utilities in conjunction with the scripting API of a commercial treatment planning system. Online evaluation of dose in proton therapy is useful to detect clinically relevant changes, guide setup, and facilitate treatment or replanning decisions.

Background: Fingolimod is approved in relapsing-remitting multiple sclerosis (RRMS) with the recommended dose of 0.5 mg daily. To tackle possible adverse events, some clinicians may reduce the dose of fingolimod, mainly in the alternate-day form. We systematically reviewed the literature for efficacy measures of this method. Methods: PubMed (Medline®), Web of Science, Embase, Scopus, and the Cochrane Library databases were searched until April 9, 2021. Clinical studies (other than case reports and case series), in English, were included. Then, publications concerning alternate dose fingolimod (including every other day, every two or three days) were selected. Those studies concerning reduced daily dose (any daily dose less than 0.5 mg/day) were excluded to focus on alternate dosing. Results: Four observational studies were included. Data on Ohtani et al. study were limited. Three other studies were of good quality based on the Newcastle-Ottawa Scale. A total of 296 patients on the standard dose were compared to 276 patients on the alternate dosage. The most common reason for switching to the alternate dose was lymphopenia, followed by elevated liver enzymes. Two studies concluded that the alternate dosing could be a safe, yet effective strategy in patients with intolerable adverse effects of daily dose. However, Zecca et al. warned about the high possibility of disease reactivation. Due to the differences in outcome measures of the studies, meta-analysis was not applicable. Conclusion: This systematic review highlights the ambiguity of evidence on safety and efficacy of alternate dosing of fingolimod, encouraging further research on the subject.

The literature considers children both a risk group for administering probiotic strains and one of the populations that can most benefit from it. Due to the health benefits associated to probiotic supplementation, this scope review sought to formulate a critical evaluation of how Lacticaseibacillus rhamnosus GG, carried in food and non-food matrices, and experimental design may affect the health promotion of infants and children. In this study, a literature search was conducted in three scientific databases: PubMed, Web of Science, and SciELO to retrieve research, published in English or Spanish, which administered L. rhamnosus GG to infants and children with any disease or in eutrophic condition. Three reviewers with an expert supervision screened 540 articles, published between 2001 and 2022, which were retrieved from the databases. The data extracted was compiled and shown in this scoping review. In total, was included, after criteria observation, 44 articles in this review. Intestinal disorders were the most frequent outcome in these studies (36.4%) and capsules, the most common vehicle for administering the probiotic strain (40.9%). Probiotic strain dose ranged from 105 to 1012 cfu/dose of L. rhamnosus GG and intervention length extended from one to more than 6 months. Food matrix showed health effects in 57.1% of the clinical trials and non-food matrix 46.7%, which indicates that the health-promoting effect of the probiotic GG strain may be equivalent between the two forms of delivery. However, the highly heterogeneous experimental designs prevent further analysis and a systematic review and meta-analysis is recommended to address just the outcomes of studies and achieve data homogeneity in order to determine which vehicle is the most suitable for health promoting.

Drug-induced liver injury (DILI) is a major safety concern; it occurs frequently; it is idiosyncratic; it cannot be adequately predicted; and a multitude of underlying mechanisms has been postulated. A number of experimental approaches to predict human DILI have been proposed utilizing in vitro screening such as inhibition of mitochondrial function, hepatobiliary transporter inhibition, reactive metabolite formation with and without covalent binding, and cellular health, but they have achieved only minimal success. Several studies have shown total administered dose alone or in combination with drug lipophilicity to be correlated with a higher risk of DILI. However, it would be best to have a predictive DILI methodology early in drug development, long before the clinical dose is known. Here we discuss the extent to which Biopharmaceutics Drug Disposition Classification System (BDDCS) defining characteristics, independent of knowing actual drug pharmacokinetics/pharmacodynamics and dose, can be used to evaluate prior published predictive proposals. Our results show that BDDCS Class 2 drugs exhibit the highest DILI severity, and that all of the short-lived published methodologies evaluated here, except when daily dose is known, do not yield markedly better predictions than BDDCS. The assertion that extensively metabolized compounds are at higher risk of developing DILI is confirmed, but can be enhanced by differentiating BDDCS Class 2 from Class 1 drugs.
CONCLUSIONS: Our published analyses suggest that comparison of proposed DILI prediction methodologies with BDDCS classification is a useful tool to evaluate the potential reliability of newly proposed algorithms, although BDDCS classification itself is not sufficiently predictive. Almost all of the predictive DILI metrics do no better than just avoiding BDDCS Class 2 drugs, although some early data with microliver platforms enabling long-enduring metabolic competency show promising results.